In principle, certain types of steroid hormones used in therapeutic procedures might beneficially be excluded from entering the central nervous system (CNS). It would be advantageous to produce derivatives of such hormones that retain their action in peripheral tissues and organs but are devoid of CNS activity. Penetration into the CNS requires that a compound be sufficiently lipophilic to cross the blood brain barrier (BBB). Therefore, to prevent penetration across the BBB it will often suffice to create an ionic drug derivative, especially a derivative that has a large charged moiety attached. However, the receptors through which steroid hormones exert their action are intracellular. Thus, it is not at all obvious that a derivative which is incapable of penetrating the BBB can in fact cross the cell membrane to reach the appropriate receptors. In other words, the cell membrane also constitutes a lipophilic barrier which hinders the passage of charged molecules.
Examples of categories of steroid receptor binding drugs that would beneficially be excluded from the CNS include: corticosteroids, which have been shown to produce neuronal loss; progestins, which are used as an adjunct to estrogen replacement therapy in order to prevent endometrial hyperplasia; and antiestrogens that are used predominantly in preventing or retarding the growth of tumors.
The use of progestins as an adjunct to estrogen in hormone replacement therapy in peri- or postmenopausal women is predicated on their opposition to the effects of estrogen. While estrogen has highly desirable actions in the brain, bone, and cardiovascular system, unopposed estrogen may be undesirable, particularly for the endometrial lining of the uterus. Progestins effectively prevent the undesirable hyperplasia of the endometrium. However, in the CNS they induce depression and hot flushes by virtue of their antiestrogenic activity. The use of progestins limited to their peripheral activity would be advantageous.
Corticosteroids are extremely useful in suppressing inflammatory reactions. Their clinical use is severely curtailed by undesirable side effects, especially during chronic administration (Sapolsky et al. (1985) J. Neurosci. 5, 1222-1227; Landfield (1987) Prog. Brain Res. 72. 279-300). Many of these adverse side effects could be avoided if these compounds were incapable of exerting their harmful action in the CNS.
Pharmaceutical therapy for breast cancer consists currently of cytotoxic and hormonal agents. Hormonal therapy was developed because, in many women, the breast cancer cells have receptors for the steroid hormone estrogen. The growth of these estrogen receptor-positive cancer cells can be stimulated by estrogen. Antiestrogen therapy attempts to reduce or stop the synthesis of estrogen or to block the action of estrogen on the cancer cell.
Among the hormonals, tamoxifen (U.S. Pat. No. 4,536,516) holds a preeminent position. Originally designed as an antiestrogen to treat breast cancer in patients with estrogen receptor-positive tumors, the drug was also found to slow the growth of breast cancer in women with estrogen receptor-negative tumors. Tamoxifen is, therefore, useful in most patients. The antiestrogen tamoxifen is particularly effective in delaying recurrence in breast cancer patients and in the palliative treatment of advanced metastatic breast cancer. It is also useful in the treatment of additional types of cancer including prostatic neoplasms (Litherland, S. et al. Cancer Treatment Reviews, 1988, 15: 183; Jordan, C., Br. J. Pharmacol., 1993, 110: 507).
Antiestrogens, including tamoxifen, compete with estrogen for receptor sites in cancerous tissues. Occupancy of the receptor site by an antiestrogen fails to elicit the further transcriptional actions generated by estrogens and blocks their activity. It is generally believed that estrogens function by binding to the target cell cytosolic receptors then moving into the cell nucleus and in turn affecting DNA transcription.
Tamoxifen and other antiestrogens also affect cellular, tumor, and organ responses by less direct mechanisms. Antiestrogens penetrate into the CNS and disrupt the normal feedback loops for hormonal balance (hypothalamus-pituitary axis) by blockading estrogen receptors in the anterior pituitary and hypothalamus. Often the physiological activity arising from altered circulating hormone levels is undesirable and leads to a variety of known side effects of antiestrogen administration. Hot flushes, which are CNS-mediated, are the most common side effect of tamoxifen (Jordan, C., ibid.).
The actions of tamoxifen and other nonsteroidal antiestrogens are complicated further by their mixed agonist-antagonist nature. Tamoxifen has partial agonist (estrogenic) activity, and the degree of agonist versus antagonist (antiestrogenic) activity is a function of the target cell (Furr, B. et al., Pharmacology & Therapeutics, 1984, 24: 127). Tamoxifen has been shown to act mainly as an antagonist in breast and brain, while its agonistic activity is more apparent in bone and the cardiovascular system.
Whereas it has been postulated that pure antiestrogenic compounds might be more effective antitumor agents, another school of thought asserts that it is advantageous to retain the partial estrogenic activity of these antitumor agents since agonistic estrogenic activity is of proven value in preventing osteoporosis, cardiovascular disorders, and postmenopausal symptoms such as hot flushes (Jordan, C., Br. J. Pharmacol., 1993, 110: 507) and possibly age-related cognitive decline and depression (Sherwin, B., Psychoneuroendocrinology, 1988, 13: 345). In particular, it has been envisaged that antiestrogen therapy could be administered prophylactically to healthy women at high risk for developing breast cancer, and large prospective clinical trials are underway to test this concept. It would be very desirable to minimize the deleterious effects of estrogen deprivation (or antagonism) in this population.
Considerable effort has been invested in the development of novel tamoxifen analogs presumed to have improved therapeutic potential, by virtue of increased selectivity as antiestrogenic compounds (e.g. U.S. Pat. No. 4,973,755; EP 0 168,175) or higher affinity for the estrogen receptor (WO 92/06068).
In various cases there have been discrepancies between the activity of tamoxifen derivatives in vitro and in vivo. For example, Foster et al. (Anticancer Drug Design, 1986, 1: 245) describes the effect of various tamoxifen hydroxy-derivatives on the growth of MCF-7 breast cancer cell line in culture. Hydroxy tamoxifen derivatives that are highly active in vitro were found to be less active than tamoxifen in vivo against a DMBA-induced estrogen receptor-positive tumor in rats, and only slightly more active against a hormone dependent mammary tumor in mice. However, when 4-hydroxy-tamoxifen itself is administered in vivo, its polarity reduces its ability to cross the cell membrane, thereby reducing its access to estrogen receptors located in the cytoplasm. Indeed, in vivo tests indicate a 4-hydroxytamoxifen to be less active than the native tamoxifen (Foster et al., J. Med. Chem., 1985, 28: 1491).
Jarman et al., Anticancer Drug Design, 1986, 1: 259-268 described the preparation and testing of tamoxifen as well as tamoxifen methiodide, ethyl bromide, and N-oxide. When tested in vitro, these derivatives were reported not to halt the proliferation of breast tumor cell lines grown in culture. The interpretation offered was that the quaternized analogs fail to enter the cells (Jarman, M. et al. ibid.; Canabrana, B., Hidalgo, A. Pharmacology, 1992, 329). It was predicted, therefore, that these compounds would be of no therapeutic value in vivo.